The cerebral metabolic rate of oxygen consumption (CMRO2) is one of the most important physiologic parameters and indicators of tissue viability. In the healthy organism CMRO2 is generally tightly regulated, varying little as a function of blood flow or environmental conditions. However, in a large number of disorders the neurometabolic-neurovascular coupling is disrupted, a condition that, if sustained leads to ischemia and irreversible damage. Positron emission tomography (PET) has been at the forefront of quantifying CMRO2. However, PET is expensive, requires administration of radiolabeled tracers, is complex in the technical set-up, and provides relatively low temporal resolution. Other methods for quantifying CMRO2 rely on measuring venous oxygen saturation levels by jugular vein oximetry and flow via optical measurements or Doppler ultrasound. In this project we propose the further development and implementation of a new method conceived in preliminary work for quantifying CMRO2, based on an integrated measurement of arterio-venous oxygen difference (AVO2D) via MRI susceptometry and simultaneous quantification of total cerebral blood flow via ungated phase contrast MRI. Target applications in view of subsequent translation to the clinic involve evaluation of patients who are at risk of systemic hypoxic injury to the brain as a result of either underoxygenation of the arterial supply or mutations of the hemoglobin gene as in sickle cell anemia. Specific Aims are: 1. Further develop an integrated magnetic resonance technique for simultaneous measurement of venous oxygen saturation and cerebral blood flow for quantification of CMRO2. 2. Test the hypothesis that the method is able to quantify the changes in CMRO2 in response to a stimulus in healthy test subjects in whom normal neurovascular and neurometabolic coupling is expected. 3. Perform two exploratory studies to assess clinical feasibility in two groups of patients in close collaboration with Pediatric Neurology at the Children's Hospital of Philadelphia. The longer-term potential and societal benefit of the proposed method is to provide a clinically practical, noninvasive, image-based means to evaluate patients with a variety of systemic conditions affecting brain metabolism, pre- and post-treatment, ranging from neurodegenerative to developmental disorders at a cost far below that of competing imaging modalities. PUBLIC HEALTH RELEVANCE: The cerebral metabolic rate of oxygen consumption (CMRO2) is one of the most fundamental physiologic parameters. Although tightly regulated in the healthy body there are numerous disorders where this regulation breaks down. The proposed MRI-based method allows rapid and reliable measurement of CMRO2 entirely noninvasively and thus could provide an effective new means for evaluating patients with impaired brain oxygen metabolism.